As a supplement to oral rehydration, symptomatic treatment of acute diarrhoea in infants.
The amount of rehydration by oral rehydration solute or intravenous rehydration administration should be adjusted depending on the intensity of the diarrhoea and the age, and the particular circumstances of the child (related disorders, etc.).

Oral use.
Hidrasec 10 mg is indicated in infants less than 13 kg.
Posology

Oral administration.

Hidrasec 10 mg is indicated in infants less than 13 kg.

Posology

The usual daily posology is established according to body weight, based on 1.5 mg/kg per dose up to a maximum of three divided daily doses.

In practice:

Number of sachet(s) per dose, depending on the infant’s body weight:

·         For an infant weighing less than 9 kg: 1 sachet, 3 times a day

·         For an infant weighing 9 to 13 kg: 2 sachets, 3 times a day.

Method of administration

The powder can be added to food or to a glass of water or feed bottle, stirring thoroughly. The infant should swallow all of the mixture immediately.

Day 1: a starting dose, then, depending on the time of the first dose, up to a maximum of three divided daily doses (including the first dose). Medication should preferably be administered at the beginning of the three main meals.

Subsequent days: three divided daily doses, preferably at the beginning of the three main meals.

Not more than three doses must be taken per day.

The treatment is to be continued until there is a return to two consecutive solid stools, but for no more than 7 days.

Specific populations

No studies have been conducted in children aged less than 3 months.

No studies have been conducted in children suffering from hepatic or renal insufficiency (see section 4.4).

Treatment with Hidrasec is only an adjuvant treatment, administered as a supplement to oral rehydration. It does not, under any circumstances, replace the latter. Rehydration must be routinely carried out in infants/children presenting acute diarrhoea to prevent or treat dehydration. It should be adjusted to compensate for the loss of water and electrolytes.

The treatment of acute diarrhoea in children is based essentially on correcting water and electrolyte losses using oral rehydration solutes and early reinstatement of feeding. The methods adopted will depend on the child’s age and the type of feeding prior to the diarrhoea.

Intravenous rehydration should be considered in the case of severe or prolonged diarrhoea, substantial vomiting, or refusal to feed.

The presence of blood or pus in the stools accompanied by fever could be indicative of diarrhoea due to invasive pathogens or other disorders. Antibacterial agents with good systemic diffusion should be administered in the case of infectious diarrhoea with clinical signs of an invasive phenomenon.

Racecadotril has not been assessed during antibiotic-related diarrhoea. Consequently, racecadotril should not be used in these cases.

Due to potentially reduced bioavailability, racecadotril should not be administered in cases of prolonged or uncontrollable vomiting.

Renal and hepatic impairment:

In the event of renal or hepatic impairment, Hidrasec should not be administered due to the lack of relevant data.

Excipients:

This medicinal product contains sucrose. It should not be given to patients with fructose intolerance, glucose-galactose malabsorption syndrome or sucrase/isomaltase deficiency (rare hereditary diseases).

This medicinal product contains 0.966 g of sucrose per sachet. If more than 5 g of sucrose (source of glucose and fructose) is contained in the daily dose of this medicinal product, this should be taken into consideration in the recommended daily allowance for patients on a low-sugar diet or presenting diabetes.

This medicinal product contains 0.2 mg of sorbitol per sachet.

Hypersensitivity:

Cutaneous reactions have been reported with the use of this medicinal product. In the majority of cases, these reactions are mild and do not require treatment. In some situations, however, these reactions can be severe and potentially life-threatening. The link associated with the administration of racecadotril cannot be entirely ruled out. If serious skin reactions appear, racecadotril must be discontinued immediately.

Cases of hypersensitivity and Quincke’s oedema have been reported in patients receiving racecadotril. These events may occur at any time during treatment.

Angioedema of the face, extremities, lips, and mucosa may appear.

Emergency treatment should be administered immediately if the angioedema is associated with an upper respiratory tract obstruction, e.g. in the region of the tongue, glottis, and/or larynx.

Racecadotril must be discontinued and the patient placed under close medical supervision, with initiation of appropriate follow-up until symptoms permanently disappear. Racecadotril must not be reintroduced.

Bradykinin-mediated angioedema:

Racecadotril or certain therapeutic classes are likely to trigger an angioedema-type vascular reaction of the face and neck, resulting from inhibition of bradykinin degradation (see section 4.8).

Angioedema can sometimes have fatal consequences due to obstruction of the airways. It can occur independently of the concomitant administration of these medicinal products in cases where the patient has had previous exposure to one of the two protagonists. The history of onset of this effect should be investigated and the need for this type of combination therapy assessed.

Concomitant administration of racecadotril with certain medicinal products increasing bradykinin

levels, especially angiotensin converting enzyme (ACE) inhibitors (e.g. perindopril and ramipril), increases the risk of bradykinin-mediated angioedema (see section 4.5)

A rigorous assessment of the benefit/risk ratio is therefore required before introducing racecadotril treatment to patients receiving angiotensin converting enzyme inhibitors (see section 4.5).

Certain medicinal products or therapeutic classes are likely to trigger an angioedema-type vascular reaction of the face and neck resulting from inhibition of bradykinin degradation.

ACE inhibitors (e.g. perindopril and ramipril) are most frequently involved and, to less of an extent, angiotensin II antagonists (e.g.: candesartan, irbesartan), so-called mTORi (mammalian target of rapamaycin inhibitor) immunosuppressants, gliptin class antidiabetic agents, racecadotril, estramustine, sacubitril and alteplase recombinant.

Angioedema can sometimes have fatal consequences due to obstruction of the airways. It can occur independently of the concomitant administration of these medicinal products in cases where the patient has had previous exposure to one of the two protagonists. The history of onset of this effect should be investigated and the need for this type of combination therapy assessed.

Association to be avoided (see also section 4.4)

+ Other medicinal products posing a risk of bradykinin-mediated angioedema (see the Medicinal products, bradykinin and angioedema section).

Others

The concomitant administration of racecadotril with loperamide or nifuroxazide does not modify the kinetic profile of racecadotril.

Pregnancy

Animal studies have not revealed any direct or indirect harmful toxic effect on reproduction. Clinical data on the use of racecadotril during pregnancy is very sparse. Therefore, as a precautionary measure, HIDRASEC should be avoided during pregnancy, regardless of trimester.

Breast-feeding

Given the lack of data regarding the diffusion of racecadotril into human milk, and because of its pharmacological properties and the immaturity of the digestive tract in newborns, HIDRASEC should not be administered during breast-feeding.

Fertility

No effect on fertility has been observed during fertility studies conducted in male and female rats.

Racecadotril has no or negligible influence on the ability to drive and use machines

Clinical studies conducted on acute diarrhoea have provided safety-in-use data in 860 infants and
children treated with racecadotril and 441 treated with placebo.
The adverse reactions listed below have been observed more frequently with racecadotril than with
placebo during clinical trials, or have been reported during the post-marketing phase.
The frequency of adverse reactions has been defined according to the following convention: very
common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to
<1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via:

National Pharmacovigilance Center (NPC)
Fax: +966-1-205-7662
Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail:npc.drug@sfda.gov.sa
Website:www.sfda.gov.sa/npc

None of the patients presented any adverse reactions in the overdose cases reported to date.

Pharmacotherapeutic group: INTESTINAL ANTISECRETORY ANTIDIARRHOEAL.
ATC code: A07XA04. (A: digestive system and metabolism). 

Racecadotril is a prodrug which must be hydrolysed into its active metabolite, thiorphan, which is an inhibitor of enkephalinase, an enzyme of the cellular membrane, present in different tissues including the intestinal epithelium.

This enzyme contributes to the hydrolysis of exogenic and endogenic peptides, such as enkephalins.

Racecadotril therefore protects enkephalins against enzymatic degradation, thus prolonging their action on the enkephalinergic synapses of the small intestine and reducing hypersecretion.

Racecadotril is a pure intestinal anti-secretory substance. It reduces the intestinal hypersecretion of water and electrolytes induced by the cholera toxin or inflammation, without impacting basal secretion. It acts as an anti-diarrhoeal agent without altering intestinal transit time.

In two paediatric clinical trials, racecadotril reduced stool weight by 40% and 46%, respectively, within the first 48 hours.

A significant reduction in the duration of the diarrhoea and in the need for rehydration was also observed.

Individual data from 1,384 boys and girls presenting acute diarrhoea of varying severity and treated as outpatients or hospital inpatients, were collected in a meta-analysis (9 randomised clinical trials, racecadotril versus placebo, as well as the oral rehydration solution).

The average age was 12 months (interquartile range: 6 to 39 months).

A total of 714 patients were less than one year old, and 670 patients were over one year old. Mean weight varied from 7.4 kg to 12.2 kg, depending on the studies. The mean overall duration of the diarrhoea post-inclusion was 2.81 days in the placebo group, and 1.75 days in the racecadotril group.

Following oral administration, racecadotril continues to display peripheral action, with no effect on the central nervous system.

A randomised, cross-over clinical study has shown that racecadotril 100 mg administered at the therapeutic dose (1 capsule) or a higher dose (4 capsules) did not prolong the QT/QTc interval in 56 healthy adult volunteers (unlike the effect observed with moxifloxacine, used as a positive control).

Absorption:

Racecadotril is rapidly absorbed following oral administration. Plasma enkephalinase activity occurs after thirty minutes.

The bioavailability of racecadotril is not changed by food, but peak activity is delayed by approximately 1.5 hours.

Distribution:

Following oral administration of 14C-labelled racecadotril to healthy volunteers, a 200-fold increase in racecadotril concentrations was recorded in the plasma compared to the blood cells, and a 3-fold increase in the plasma versus total blood volume. There is no significant binding to blood cells.

In the plasma, the mean apparent volume of distribution of 66.4 L/kg demonstrates moderate distribution of 14C in the other tissues.

Ninety percent of the active metabolite of racecadotril, tiorfan, (RS)-N-(1-oxo-2-(mercaptomethyl)-3-

phenylpropyl) glycine, is bound to plasma proteins, mainly albumin.

The pharmacokinetic properties of racecadotril do not alter during repeated dosing or in elderly subjects.

The extent and duration of action of racecadotril are dose-dependent. Peak concentrations are reached after approximately 2.5 hours, corresponding to 90% inhibition of the enzymatic activity for the dose of 1.5 mg/kg.

Plasma enkephalinase activity continues for around 8 hours following the administration of 100 mg.

Biotransformation

The biological half-life of racecadotril, determined on the basis of enkephalinase plasma inhibition, is 3 hours.

Racecadotril is rapidly hydrolysed into tiorfan (RS)-N-(1-oxo-2-(mercaptomethyl)-3-phenylpropyl) glycine, its active metabolite, which itself transforms into inactive metabolites S-methylthiorphan sulfoxide, S methyl tiorfan, 2-methane sulfinylmethyl propionic acid and 2-methylsulfanylmethyl propionic acid, which are all formed following more than 10% systemic exposure to the parent molecule.

Other minor metabolites have also been detected and quantified in the urine and faecal matter. Repeated dosing with racecadotril does not cause accumulation in the body.

The in-vitro data show that racecadotril/tiorfan and its four major inactive metabolites do not significantly inhibit cytochrome CYP 3A4 isoforms, 2D6, 2C9, 1A2 and 2C19.

The in-vitro data show that racecadotril/tiorfan and its four major inactive metabolites do not significantly induce CYP cytochrome isoforms (family 3A, 2A6, 2B6, 2C9/2C19, family 1A, 2E1) and the enzymes which bind to glucuronyl transferase.

Racecadotril does not change the protein binding of products which are strongly bound to proteins, such as tolbutamide, warfarin, niflumic acid, digoxin or phenytoin.

In patients with hepatic insufficiency (cirrhosis, Child-Pugh B), the metabolite’s kinetic profile displays the same Tmax and T^1/2 values and lower Cmax (-65 %) and area under the curve (-29 %) compared to healthy subjects.

In patients with severe renal insufficiency (creatinine clearance between 11 and 39 ml/min), the metabolite’s kinetic profile displays a lower Cmax (-49 %) and larger area under the curve (+15 %) and T^1/2 compared to healthy volunteers (creatinine clearance > 70 ml/min).

The pharmacodynamic results obtained in the paediatric population are similar to those of the adult population, with Cmax being reached 2.5 hours post-dose. There is no accumulation following administration of repeated doses every 8 hours, for 7 days.

Elimination

Racecadotril is eliminated via its active and inactive metabolites. Elimination occurs primarily via the kidneys (81.4%) and, to a lesser extent, in the faeces (about 8%). There is no significant elimination via the pulmonary route (less than 1% of the dose).

Four-week chronic toxicity studies conducted in monkeys and dogs, which are beneficial for assessing the duration of treatment in humans, did not highlight any effect at doses of up to 1,250 mg/kg/day and 200 mg/kg, which correspond to safety margins of 625 and 62, respectively (in relation to humans).

Racecadotril did not prove to be immunotoxic to mice treated for 1 month.

Longer exposure (one year) to monkeys revealed generalised infections and reduced antibody response on vaccination (at a dose of 500 mg/kg/day) and no infection/immune suppression at 120 mg/kg/day.

Similarly, a few infectious/immune responses were noted in dogs receiving 200 mg/kg/day for 26 weeks. The clinical significance is not known: see section 4.8.

No mutagenic or clastogenic effects of racecadotril were observed during standard in-vivo and in vitro testing.

No carcinogenicity tests were conducted since treatment is administered short term.

Reproductive and development toxicity tests (pre-embryonic and fertility development, antenatal and post-natal development, embryo-foetal development studies) have not revealed any racecadotril-specific effect.

Other preclinical effects (such as severe anaemia, probably aplastic, increased diuresis, ketonuria and diarrhoea) were observed only after exposure sufficiently exceeding the maximum exposure in humans. Their clinical significance is not known.

A toxicity study conducted in young rats did not reveal any evidence of a significant racecadotril related effect at doses up to 160 mg/kg/day, which is 35 times higher than the recommended paediatric dose (e.g. 4.5 mg/kg/day).

Despite immature renal function in children under 1 year old, higher levels of exposure are not expected in this particular group.

No harmful effects on the central nervous system, cardiovascular system or respiratory function have been highlighted in other pharmacology safety studies.

In animals, racecadotril potentiates the effect of butyl hyoscine on the intestinal tract and on the anticonvulsant effect of phenytoin.

Sucrose

 anhydrous colloidal silica

30% polyacrylate dispersion

 apricot flavouring (vanillin, gamma undecalactone

gamma nonalactone

 allyl caproate

lemon

 neroli

 orange

 gum arabic

maltodextrin
sorbitol 

Not applicable

This medicinal product does not require any special precautions for storage.

1 g powder in pouches (PE/paper/aluminium); box of 16

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with current legislation.